COMPUTER SIMULATIONS OF THE INTERACTION OF CIGUATOXIN 3C, BREVENAL AND ent-BREVENAL LADDER POLYETHERS WITH A HOMOLOGY MODEL OF THE VOLTAGE-GATED Kv1.5 POTASSIUM CHANNEL

Abstract

The interaction of ladder polyethers of marine origin, like ciguatoxin 3C and brevenal, as well as hypothetic ent-brevenal, with the human voltage-gated Kv1.5 potassium ion channel is investigated in this work using homology modeling, automated docking, and energy scoring from molecular dynamics (MD) simulations. A 3D homology model of the pore region of the Kv1.5 channel, previously developed from the 2.9 Å resolution crystal structure of the mammalian Kv1.2 channel — which has a very similar pore sequence — is used here. While ciguatoxin 3C did not enter the pore, both brevenal and ent-brevenal were found into the pore, the latter one with the best score. Binding is attended by notable strain in the ligands, and the corresponding energy increase was evaluated for ent-brevenal by self consistent field (SCF) and density functional theory (DFT) procedures. Egress of ent-brevenal from the pore, as a microscopical reversal of the ingress, was investigated by a smart form of biased MD simulations. While this study indicates ample room and attractive interactions for both brevenal and its enantiomer into the pore, whether these molecules will be found to inhibit voltage-gated potassium ion currents depends upon the barriers in the real system to access the pore, with their thermodynamic and kinetic requirements.